Non-competitive N-methyl-D-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons.
The response of ventral tegmental (VTA) A10 dopamine neurons to a series of compounds covering the spectrum from high-affinity phencyclidine receptor ligands (MK-801, PCP) to high-affinity sigma-receptor ligands [+)-pentazocine, DTG) was measured using single-unit extracellular recording techniques in the rat. Dose-response comparisons revealed that MK-801 was 3, 6, 19 and 119 times more potent at activating A10 neurons than PCP, (+)-SKF-10,047, ketamine and (+)-pentazocine, respectively. DTG (1,3-di-o-tolylguanidine), the most selective sigma-ligand, and U50,488H, a kappa-opiate, failed to produce any stimulation of firing. Also, pretreatment with haloperidol, a potent sigma-receptor ligand, did not prevent MK-801-induced excitations. Thus, the activation of the A10-mesolimbic-mesocortical dopamine pathways by PCP, PCP-like drugs and sigma-psychotomimetics is mediated by the PCP receptor, not the haloperidol-sensitive sigma-receptor, with potencies directly correlated to their activity as non-competitive N-methyl-D-aspartate (NMDA) antagonists.
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Department of Pharmacology, University of Arizona, College of Medicine, Tucson 85724.
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D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D013681:Tegmentum Mesencephali / Q000166:cytology / Q000502:physiology*
D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D006220:Haloperidol; D004298:Dopamine